Novel method of diagnosing, monitoring, staging, imaging and treating various cancers

ABSTRACT

The present invention provides a new method for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating selected cancers including gynecologic cancers such as breast, ovarian, uterine and endometrial cancer and lung cancer.

FIELD OF THE INVENTION

This invention relates, in part, to newly developed assays fordetecting, diagnosing, monitoring, staging, prognosticating, imaging andtreating various cancers, particularly gynecologic cancer includingovarian, uterine endometrial and breast cancer, and lung cancer.

BACKGROUND OF TEE INVENTION

The American Cancer Society has estimated that over 560,000 Americanswill die this year from cancer. Cancer is the second leading cause ofdeath in the United States, exceeded only by heart disease. It has beenestimated that over one million new cancer cases will be diagnosed in1999 alone.

In women, gynecologic cancers account for more than one-fourth of themalignancies.

Of the gynecologic cancers, breast cancer is the most common. Accordingto the Women's Cancer Network, 1 out of every 8 women in the UnitedStates is as risk of developing breast cancer, and 1 out of every 28women are at risk of dying from breast cancer. Approximately 77% ofwomen diagnosed with breast cancer are over the age of 50. However,breast cancer is the leading cause of death in women between the ages of40 and 55.

Carcinoma of the ovary is another very common gynecologic cancer.Approximately one in 70 women will develop ovarian cancer during herlifetime. An estimated 14,500 deaths in 1995 resulted from ovariancancer. It causes more deaths than any other cancer of the femalereproductive system. Ovarian cancer often does not cause any noticeablesymptoms. Some possible warning signals, however, are an enlargedabdomen due to an accumulation of fluid or vague digestive disturbances(discomfort, gas or distention) in women over 40; rarely there will beabnormal vaginal bleeding. Periodic, complete pelvic examinations areimportant; a Pap test does not detect ovarian cancer. Annual pelvicexams are recommended for women over 40.

Also common in women is endometrial cancer or carcinoma of the lining ofthe uterus. According to the Women's Cancer Center endometrial canceraccounts for approximately 13% of all malignancies in women. There areabout 34,000 cases of endometrial cancer diagnosed in the United Stateseach year.

Uterine sarcoma is another type of uterine malignancy much more rare ascompared to other gynecologic cancers. In uterine sarcoma, malignantcells start growing in the muscles or other supporting tissues of theuterus. Sarcoma of the uterus is different from cancer of theendometrium, a disease in which cancer cells start growing in the liningof the uterus. This uterine cancer usually begins after menopause. Womenwho have received therapy with high-dose X-rays (external beam radiationtherapy) to their pelvis are at a higher risk to develop sarcoma of theuterus. These X-rays are sometimes given to women to stop bleeding fromthe uterus.

Lung cancer is the second most prevalent type of cancer for both men andwomen in the United States and is the most common cause of cancer deathin both sexes. Lung cancer can result from a primary tumor originatingin the lung or a secondary tumor which has spread from another organsuch as the bowel or breast. Primary lung cancer is divided into threemain types; small cell lung cancer; non-small cell lung cancer; andmesothelioma. Small cell lung cancer is also called “Oat Cell” lungcancer because the cancer cells are a distinctive oat shape. There arethree types of non-small cell lung cancer. These are grouped togetherbecause they behave in a similar way and respond to treatmentdifferently to small cell lung cancer. The three types are squamous cellcarcinoma, adenocarcinoma, and large cell carcinoma. Squamous cellcancer is the most common type of lung cancer. It develops from thecells that line the airways. Adenocarcinoma also develops from the cellsthat line the airways. However, adenocarcinoma develops from aparticular type of cell that produces mucus (phlegm). Large cell lungcancer has been thus named because the cells look large and rounded whenthey are viewed under a microscope. Mesothelioma is a rare type ofcancer which affects the covering of the lung called the pleura.Mesothelioma is often caused by exposure to asbestos.

Procedures used for detecting, diagnosing, monitoring, staging, andprognosticating each of these types of cancer are of critical importanceto the outcome of the patient. In all cases, patients diagnosed early indevelopment of the cancer generally have a much greater five-yearsurvival rate as compared to the survival rate for patients diagnosedwith a cancer which has metastasized. New diagnostic methods which aremore sensitive and specific for early detection of various types ofcancer are clearly needed.

In the present invention methods are provided for detecting, diagnosing,monitoring, staging, prognosticating, in vivo imaging and treatingselected cancers including, but not limited to, gynecologic cancers suchas ovarian, breast endometrial and/or uterine cancer, and lung cancervia detection of a Cancer Specific Genes (CSGs). Nine CGSs have beenidentified and refer, among other things, to native proteins expressedby the genes comprising-the polynucleotide sequences of any of SEQ IDNO: 1, 2, 3, 4, 5, 6, 7, 8 or 9. In the alternative, what is meant bythe nine CSGs as used herein, means the native mRNAs encoded by thegenes comprising any of the polynucleotide sequences of SEQ ID NO: 1, 2,3, 4, 5, 6, 7, 8 or 9 or it can refer to the actual genes comprising anyof the polynucleotide sequences of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or9. Fragments of the CSGs such as those depicted in SEQ ID NO:10, 11, 12,13 or 14 can also be detected.

Other objects, features, advantages and aspects of the present inventionwill become apparent to those of skill in the art from the followingdescription. It should be understood, however, that the followingdescription and the specific examples, while indicating preferredembodiments of the invention are given by way of illustration only.Various changes and modifications within the spirit and scope of thedisclosed invention will become readily apparent to those skilled in theart from reading the following description and from reading the otherparts of the present disclosure.

SUMMARY OF THE INVENTION

Toward these ends, and others, it is an object of the present inventionto provide a method for diagnosing the presence of selected cancers byanalyzing for changes in levels of CSG in cells, tissues or bodilyfluids compared with levels of CSG in preferably the same cells,tissues, or bodily fluid type of a normal human control, wherein achange in levels of CSG in the patient versus the normal human controlis associated with the selected cancer. For the purposes of thisinvention, by “selected cancer” it is meant to include gynecologiccancers such as ovarian, breast, endometrial and uterine cancer, andlung cancer.

Further provided is a method of diagnosing metastatic cancer in apatient having a selected cancer which is not known to have metastasizedby identifying a human patient suspected of having a selected cancerthat has metastasized; analyzing a sample of cells, or bodily fluid fromsuch patient for CSG; comparing the CSG levels in such cells, tissues,or bodily fluid with levels of CSG in preferably the same cells,tissues, or bodily fluid type of a normal human control, wherein anincrease in CSG levels in the patient versus the normal human control isassociated with a cancer which has metastasized.

Also provided by the invention is a method of staging selected cancersin a human patient by identifying a human patient having such cancer;analyzing a sample of cells, tissues, or bodily fluid from such patientfor CSG; comparing CSG levels in such cells, tissues, or bodily fluidwith levels of CSG in preferably the same cells tissues, or bodily fluidtype of a normal human control sample, wherein an increase in CSG levelsin the patient versus the normal human control is associated with acancer which is progressing and a decrease in the levels of CSG isassociated with a cancer which is regressing or in remission.

Further provided is a method of monitoring selected cancers in patientsfor the onset of metastasis. The method comprises identifying a humanpatient having a selected cander that is not known to have metastasized;periodically analyzing a sample of cells, tissues, or bodily fluid fromsuch patient for CSG; comparing the CSG levels in such cells, tissues,or bodily fluid with levels of CSG in preferably the same cells,tissues, or bodily fluid type of a normal human control sample, whereinan increase in CSG levels in the patient versus the normal human controlis associated with a cancer which has metastasized.

Further provided is a method of monitoring the change in stage ofselected cancers in humans having such cancer by looking at levels ofCSG. The method comprises identifying a human patient having a selectedcancer; periodically analyzing a sample of cells, tissues, or bodilyfluid from such patient for CSG; comparing the CSG levels in such cells,tissue, or bodily fluid with levels of CSG in preferably the same cells,tissues, or bodily fluid type of a normal human control sample, whereinan increase in CSG levels in the patient versus the normal human controlis associated with a cancer which is progressing and a decrease in thelevels of CSG is associated with a cancer which is regressing or inremission.

Further provided are antibodies against CSG or fragments of suchantibodies which can be used to detect or image localization of CSG in apatient for the purpose of detecting or diagnosing selected cancers.Such antibodies can be polyclonal or monoclonal, or prepared bymolecular biology techniques. The term “antibody”, as used herein andthroughout the instant specification is also meant to include aptamersand single-stranded oligonucleotides such as those derived from an invitro evolution protocol referred to as SELEX and well known to thoseskilled in the art. Antibodies can be labeled with a variety ofdetectable labels including, but not limited to, radioisotopes andparamagnetic metals. These antibodies or fragments thereof can also beused as therapeutic agents in the treatment of diseases characterized byexpression of a CSG. In therapeutic applications, the antibody can beused without or with derivatization to a cytotoxic agent such as aradioisotope, enzyme, toxin, drug or a prodrug.

Other objects, features, advantages and aspects of the present inventionwill become apparent to those of skill in the art from the followingdescription. It should be understood, however, that the followingdescription and the specific examples, while indicating preferredembodiments of the invention, are given by way of illustration only.Various changes and modifications within the spirit and scope of thedisclosed invention will become readily apparent to those skilled in theart from reading the following description and from reading the otherparts of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to diagnostic assays and methods, bothquantitative and qualitative for detecting, diagnosing, monitoring,staging and prognosticating selected cancers by comparing levels of CSGwith those of CSG in a normal human control. What is meant by levels ofCSG as used herein is levels of the native protein expressed by the genecomprising the polynucleotide sequence of any of SEQ ID NO: 1, 2, 3, 4,5, 6, 7, 8 or 9. In the alternative, what is meant by levels of CSG asused herein is levels of the native mRNA encoded by the gene comprisingany of the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8or 9 or levels of the gene comprising any of the polynucleotidesequences of SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8 or 9. Fragments of CSGssuch as those depicted in SEQ ID NO: 10, 11, 12, 13 and 14 can also bedetected. Such levels are preferably measured in at least one of cells,tissues and/or bodily fluids, including determination of normal andabnormal levels. Thus, for instance, a diagnostic assay in accordancewith the invention for diagnosing over-expression of CSG proteincompared to normal control bodily fluids, cells, or tissue samples maybe used to diagnose the presence of selected cancers. What is meant by“selected cancers” as used herein is a gynecologic cancer such asovarian, breast, endometrial or uterine cancer, or lung case.

Any of the 9 CSGs can be measured alone in the methods of the invention,or all together or any combination thereof. However, for methodsrelating to gynecologic cancers including ovarian, breast, endometrialand uterine cancer, it is preferred that levels of CSG comprising SEQ IDNO:1 or a fragment thereof be determined. Exemplary fragments of thisCSG which can be detected are depicted in SEQ ID NO: 10, 11, 12, and 13.For methods relating to lung cancer and gynecologic cancers includingovarian, endometrial and uterine, it is preferred that levels of CSGcomprising SEQ ID NO:2 or 9 be determined. Fragments of this CSG such asthat depicted in SEQ ID NO:14 can also be detected. For methods relatingto ovarian cancer, determination of levels of CSG comprising SEQ ID NO:3is also preferred.

All the methods of the present invention may optionally includemeasuring the levels of other cancer markers as well as CSG. Othercancer markers, in addition to CSG, useful in the present invention willdepend on the cancer being tested and are known to those of skill in theart.

Diagnostic Assays

The present invention provides methods for diagnosing the presence ofselected cancers by analyzing for changes in levels of CSG in cells,tissues or bodily fluids compared with levels of CSG in cells, tissuesor bodily fluids of preferably the same type from a normal humancontrol, wherein a change in levels of CSG in the patient versus thenormal human control is associated with the presence of a selectedcancer.

Without limiting the instant invention, typically, for a quantitativediagnostic assay a positive result indicating the patient being testedhas cancer is one in which cells, tissues or bodily fluid levels of thecancer marker, such as CSG, are at least two times higher, and mostpreferably are at least five times higher, than in preferably the samecells, tissues or bodily fluid of a normal human control.

The present invention also provides a method of diagnosing metastases ofselected cancers in a patient having a selected cancer which has not yetmetastasized for the onset of metastasis. In the method of the presentinvention, a human cancer patient suspected of having a selected cancerwhich may have metastasized (but which was not previously known to havemetastasized) is identified. This is accomplished by a variety of meansknown to those of skill in the art. For example, in the case of ovariancancer, patients are typically diagnosed with ovarian cancer followingsurgical staging and monitoring of CA125 levels. Traditional detectionmethods are also available and well known for other selected cancerswhich can be diagnosed by determination of CSG levels in a patient.

In the present invention, determining the presence of CSG levels incells, tissues or bodily fluid, is particularly useful fordiscriminating between a selected cancer which has not metastasized anda selected cancer which has metastasized. Existing techniques havedifficulty discriminating between cancers which have metastasized andcancers which have not metastasized and proper treatment selection isoften dependent upon such knowledge.

In the present invention, the cancer marker levels measured in suchcells, tissues or bodily fluid is CSG, and are compared with levels ofCSG in preferably the same cells, tissue or bodily fluid type of anormal human control. That is, if the cancer marker being observed isCSG in serum, this level is preferably compared with the level of CSG inserum of a normal human patient. An increase in the CSG in the patientversus the normal human control is associated with a cancer which hasmetastasized.

Without limiting the instant invention, typically, for a quantitativediagnostic assay a positive result indicating the cancer in the patientbeing tested or monitored has metastasized is one in which cells,tissues or bodily fluid levels of the cancer marker, such as CSG, are atleast two times higher, and most preferably are at least five timeshigher, than in preferably the same cells, tissues or bodily fluid of anormal patient.

Normal human control as used herein includes a human patient withoutcancer and/or non cancerous samples from the patient; in the methods fordiagnosing or monitoring for metastasis, normal human control may alsoinclude samples from a human patient that is determined by reliablemethods to have a selected cancer which has not metastasized.

Staging

The invention also provides a method of staging selected cancers inhuman patients. The method comprises identifying a human patient havinga selected cancer and analyzing a sample of cells, tissues or bodilyfluid from such human patient for CSG. Then, the method compares CSGlevels in such cells, tissues or bodily fluid with levels of CSG inpreferably the same cells, tissues or bodily fluid type of a normalhuman control sample, wherein an increase in CSG levels in the humanpatient versus the normal human control is associated with a cancerwhich is progressing and a decrease in the levels of CSG is associatedwith a cancer which is regressing or in remission.

Monitoring

Further provided is a method of monitoring selected cancers in humansfor the onset of metastasis. The method comprises identifying a humanpatient having a selected cancer that is not known to have metastasized;periodically analyzing a sample of cells, tissues or bodily fluid fromsuch human patient for CSG; comparing the CSG levels in such cells,tissues or bodily fluid with levels of CSG in preferably the same cells,tissues or bodily fluid type of a normal human control sample, whereinan increase in CSG levels in the human patient versus the normal humancontrol is associated with a cancer which has metastasized.

Further provided by this invention is a method of monitoring the changein stage of selected cancers in humans having such cancers. The methodcomprises identifying a human patient having a selected cancer;periodically analyzing a sample of cells, tissues or bodily fluid fromsuch human patient for CSG; comparing the CSG levels in such cells,tissues or bodily fluid with levels of CSG in preferably the same cells,tissues or bodily fluid type of a normal human control sample, whereinan increase in CSG levels in the human patient versus the normal humancontrol is associated with a cancer which is progressing in stage and adecrease in the levels of CSG is associated with a cancer which isregressing in stage or in remission.

Monitoring such patient for onset of metastasis is periodic andpreferably done on a quarterly basis. However, this may be more or lessfrequent depending on the cancer, the particular patient, and the stageof the cancer.

Assay Techniques

Assay techniques that can be used to determine levels of geneexpression, such as CSG of the present invention, in a sample derivedfrom a patient are well known to those of skill in the art. Such assaymethods include radioimmunoassays, reverse transcriptase PCR (RT-PCR)assays, immunohistochemistry assays, in situ hybridization assays,competitive-binding assays, Western Blot analyses, ELISA assays andproteomic approaches. Among these, ELISAs are frequently preferred todiagnose a gene's expressed protein in biological fluids.

An ELISA assay initially comprises preparing an antibody, if not readilyavailable from a commercial source, specific to CSG, preferably amonoclonal antibody. In addition a reporter antibody generally isprepared which binds specifically to CSG. The reporter antibody isattached to a detectable reagent such as radioactive, fluorescent orenzymatic reagent, for example horseradish peroxidase enzyme or alkalinephosphatase.

To carry out the ELISA, antibody specific to CSG is incubated on a solidsupport, e.g. a polystyrene dish, that binds the antibody. Any freeprotein binding sites on the dish are then covered by incubating with anon-specific protein such as bovine serum albumin. Next, the sample tobe analyzed is incubated in the dish, during which time CSG binds to thespecific antibody attached to the polystyrene dish. Unbound sample iswashed out with buffer. A reporter antibody specifically directed to CSGand linked to horseradish peroxidase is placed in the dish resulting inbinding of the reporter antibody to any monoclonal antibody bound toCSG. Unattached reporter antibody is then washed out. Reagents forperoxidase activity, including a colorimetric substrate are then addedto the dish. Immobilized peroxidase, linked to CSG antibodies, producesa colored reaction product. The amount of color developed in a giventime period is proportional to the amount of CSG protein present in thesample. Quantitative results typically are obtained by reference to astandard curve.

A competition assay may be employed wherein antibodies specific to CSGattached to a solid support and labeled CSG and a sample derived fromthe host are passed over the solid support and the amount of labeldetected attached to the solid support can be correlated to a quantityof CSG in the sample.

Nucleic acid methods may be used to detect CSG mRNA as a marker forselected cancers. Polymerase chain reaction (PCR) and other nucleic acidmethods, such as ligase chain reaction (LCR) and nucleic acid sequencebased amplification (NASABA), can be used to detect malignant cells fordiagnosis and monitoring of the various selected malignancies. Forexample, reverse-transcriptase PCR (RT-PCR) is a powerful techniquewhich can be used to detect the presence of a specific mRNA populationin a complex mixture of thousands of other mRNA species. In RT-PCR, anmRNA species is first reverse transcribed to complementary DNA (cDNA)with use of the enzyme reverse transcriptase; the cDNA is then amplifiedas in a standard PCR reaction. RT-PCR can thus reveal by amplificationthe presence of a single species of mRNA. Accordingly, if the mRNA ishighly specific for the cell that produces it, RT-PCR can be used toidentify the presence of a specific type of cell.

Hybridization to clones or oligonucleotides arrayed on a solid support(i.e. gridding) can be used to both detect the expression of andquantitate the level of expression of that gene. In this approach, acDNA encoding the CSG gene is fixed to a substrate. The substrate may beof any suitable type including but not limited to glass, nitrocellulose,nylon or plastic. At least a portion of the DNA encoding the CSG gene isattached to the substrate and then incubated with the analyte, which maybe RNA or a complementary DNA (cDNA) copy of the RNA, isolated from thetissue of interest. Hybridization between the substrate bound DNA andthe analyte can be detected and quantitated by several means includingbut not limited to radioactive labeling or fluorescence labeling of theanalyte or a secondary molecule designed to detect the hybrid.Quantitation of the level of gene expression can be done by comparisonof the intensity of the signal from the analyte compared with thatdetermined from known standards. The standards can be obtained by invitro transcription of the target gene, quantitating the yield, and thenusing that material to generate a standard curve.

Of the proteomic approaches, 2D electrophoresis is a technique wellknown to those in the art. Isolation of individual proteins from asample such as serum is accomplished using sequential separation ofproteins by different characteristics usually on polyacrylamide gels.First, proteins are separated by size using an electric current. Thecurrent acts uniformly on all proteins, so smaller proteins move fartheron the gel than larger proteins. The second dimension applies a currentperpendicular to the first and separates proteins not on the basis ofsize but on the specific electric charge carried by each protein. Sinceno two proteins with different sequences are identical on the basis ofboth size and charge, the result of a 2D separation is a square gel inwhich each protein occupies a unique spot. Analysis of the spots withchemical or antibody probes, or subsequent protein microsequencing canreveal the relative abundance of a given protein and the identity of theproteins in the sample.

The above tests can be carried out on samples derived from a variety ofpatients' cells, bodily fluids and/or tissue extracts (homogenates orsolubilized tissue) such as from tissue biopsy and autopsy material.Bodily fluids useful in the present invention include blood, urine,saliva or any other bodily secretion or derivative thereof. Blood caninclude whole blood, plasma, serum or any derivative of blood.

In Vivo Antibody Use

Antibodies against CSG can also be used in vivo in patients suspected ofsuffering from a selected cancer including lung cancer or gynecologiccancers such as ovarian, breast, endometrial or uterine cancer.Specifically, antibodies against a CSG can be injected into a patientsuspected of having a selected cancer for diagnostic and/or therapeuticpurposes. The use of antibodies for in vivo diagnosis is well known inthe art. For example, antibody-chelators labeled with Indium-111 havebeen described for use in the radioimmunoscintographic imaging ofcarcinoembryonic antigen expressing tumors (Sumerdon et al. Nucl. Med.Biol. 1990 17: 247-254). In particular, these antibody-chelators havebeen used in detecting tumors in patients suspected of having recurrentcolorectal cancer (Griffin et al. J. Clin. One. 1991 9: 631-640).Antibodies with paramagnetic ions as labels for use in magneticresonance imaging have also been described (Lauffer, R. B. MagneticResonance in Medicine 1991 22: 339-342). Antibodies directed againstCSGs can be used in a similar manner. Labeled antibodies against a CSGcan be injected into patients suspected of having a selected cancer forthe purpose of diagnosing or staging of the disease status of thepatient. The label used will be selected in accordance with the imagingmodality to be used. For example, radioactive labels such as Indium-111,Technetium-99m or Iodine-131 can be used for planar scans or singlephoton emission computed tomography (SPECT). Positron emitting labelssuch as Fluorine-19 can be used in positron emission tomography.Paramagnetic ions such as Gadlinium (III) or Manganese (II) can used inmagnetic resonance imaging (MRI). Localization of the label permitsdetermination of the spread of the cancer. The amount of label within anorgan or tissue also allows determination of the presence or absence ofcancer in that organ or tissue.

For patients diagnosed with a selected cancer, injection of an antibodyagainst a CSG can also have a therapeutic benefit. The antibody mayexert its therapeutic effect alone.

Alternatively, the antibody is conjugated to a cytotoxic agent such as adrug, toxin or radionuclide to enhance its therapeutic effect. Drugmonoclonal antibodies have been described in the art for example byGarnett and Baldwin, Cancer Research 1986 46: 2407-2412. The use oftoxins conjugated to monoclonal antibodies for the therapy of variouscancers has also been described by Pastan et al. Cell 1986 47: 641-648.Yttrium-90 labeled monoclonal antibodies have been: described formaximization of dose delivered to the tumor while limiting toxicity tonormal tissues' (Goodwin and Meares Cancer Supplement 1997 80:2675-2680). Other cytotoxic radionuclides including, but not limited toCopper-67, Iodine-131 and Rhenium-186 can also be used for labeling ofantibodies against CSGs.

Antibodies which can be used in these in vivo methods include bothpolyclonal and monoclonal antibodies and antibodies prepared viamolecular biology techniques. Antibody fragments and aptamers andsingle-stranded oligonucleotides such as those derived from an in vitroevolution protocol referred to as SELEX and well known to those skilledin the art can also be used.

The present invention is further described by the following examples.These examples are provided solely to illustrate the invention byreference to specific embodiments. The exemplifications, whileillustrating certain aspects of the invention do not portray thelimitations or circumscribe the scope of the disclosed invention.

EXAMPLES Example 1

Identification of CSGs were carried out by a systematic analysis of datain the LIFESEQ database available from Incyte Pharmaceuticals, PaloAlto, Calif., using the data mining Cancer Leads Automatic SearchPackage (CLASP) developed by diaDexus LLC, Santa Clara, Calif.

The CLASP performs the following steps: selection of highly expressedorgan specific genes based on the abundance level of the correspondingEST in the targeted organ versus all the other organs; analysis of theexpression level of each highly expressed organ specific genes innormal, tumor tissue, disease tissue and tissue libraries associatedwith tumor or disease. Selection of the candidates demonstratingcomponent ESTs were exclusively or more frequently found in tumorlibraries. The CLASP allows the identification of highly expressed organand cancer specific genes. A final manual in depth evaluation is thenperformed to finalize the CSGs selection. TABLE 1 CSG Sequences SEQ IDNO: Clone ID Gene ID 1 16656542 234617 2  1283171 332459 3  1649377481154 4 236044H1 none assigned 5 none assigned 255687 6 none assigned251313 7 none assigned  12029 8 none assigned 251804

The following examples are carried out using standard techniques, whichare well known and routine to those of skill in the art, except whereotherwise described in detail. Routine molecular biology techniques ofthe following example can be carried out as described in standardlaboratory manuals, such as Sambrook et al., MOLECULAR CLONING: ALABORATORY MANUAL, 2nd Ed.; Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y. (1989).

Example 2 Relative Quantitation of Gene Expression

Real-Time quantitative PCR with fluorescent Taqman probes is aquantitation detection system utilizing the 5′-3′ nuclease activity ofTaq DNA polymerase. The method uses an internal fluorescentoligonucleotide probe (Taqman) labeled with a 5′ reporter dye and adownstream, 3′ quencher dye. During PCR, the 5′-3′ nuclease activity ofTaq DNA polymerase releases the reporter, whose fluorescence can then bedetected by the laser detector of the Model 7700 Sequence DetectionSystem (PE Applied Biosystems, Foster City, Calif., USA).

Amplification of an endogenous control is used to standardize the amountof sample RNA added to the reaction and normalize for ReverseTranscriptase (RT) efficiency. Either cyclophilin,glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or 18S ribosomal RNA(rRNA) is used as this endogenous control. To calculate relativequantitation between all the samples studied, the target RNA levels forone sample were used as the basis for comparative results (calibrator).Quantitation relative to the “calibrator” can be obtained using thestandard curve method or the comparative method (User Bulletin #2: ABIPRISM 7700 Sequence Detection System).

The tissue distribution and the level of the target gene for everyexample in normal and cancer tissue were evaluated. Total RNA wasextracted from normal tissues, cancer tissues, and from cancers and thecorresponding matched adjacent tissues. Subsequently, first strand cDNAwas prepared with reverse transcriptase and the polymerase chainreaction was done using primers and Taqman probe specific to each targetgene. The results are analyzed using the ABI PRISM 7700 SequenceDetector. The absolute numbers are relative levels of expression of thetarget gene in a particular tissue compared to the calibrator tissue.

Measurement of Ovr110; Clone ID16656542; Gene ID 234617 (SEQ ID NO:1,10, 11, 12 or 13)

The absolute numbers depicted in Table 2 are relative levels ofexpression of Ovr110 (SEQ ID NO:1 or a fragment thereof as depicted inSEQ ID NO:10, 11, 12, or 13) in 12 normal different tissues. All thevalues are compared to normal stomach (calibrator). These RNA samplesare commercially available pools, originated by pooling samples of aparticular tissue from different individuals. TABLE 2 Relative Levels ofOvr110 Expression in Pooled Samples Tissue NORMAL colon 0.00 endometrium8.82 kidney 7.19 liver 0.36 ovary 1.19 pancreas 21.41 prostate 2.79small intestine 0.03 spleen 0.00 00000000000000stoma 1.00 testis 8.72uterus 0.93

The relative levels of expression in Table 2 show that Ovr110 isexpressed at comparable levels in most of the normal tissues analyzed.Pancreas, with a relative expression level of 21.41, endometrium (8.82),testis (8.72), and kidney (7.19) are the only tissues expressing highlevels of Ovr110 mRNA.

The absolute numbers in Table 2 were obtained analyzing pools of samplesof a particular tissue from different individuals. They can not becompared to the absolute numbers originated from RNA obtained fromtissue samples of a single individual in Table 3.

The absolute numbers depicted in Table 3 are relative levels ofexpression of Ovr110 in 73 pairs of matching samples. All the values arecompared to normal stomach (calibrator). A matching pair is formed bymRNA from the cancer sample for a particular tissue and mRNA from thenormal adjacent sample for that same tissue from the same individual. Inaddition, 15 unmatched cancer samples (from ovary and mammary gland) and14 unmatched normal samples (from ovary and mammary gland) were alsotested. TABLE 3 Relative Levels of Ovr110 Expression in IndividualSamples Matching Normal Sample ID Tissue Cancer Adjacent Normal Ovr103XOvary 1 86.22 0.53 Ovr10400 Ovary 2 168.31 Ovr1157 Ovary 3 528.22 Ovr63AOvary 4 1.71 Ovr773O Ovary 5 464.65 Ovr1005O Ovary 6 18.32 Ovr1028 Ovary7 7.78 Ovr1118 Ovary 8 0.00 Ovr130X Ovary 9 149.09 Ovr638A Ovary 10 3.14OvrA1B Ovary 11 21.26 OvrA1C Ovary 12 1.83 OvrC360 Ovary 13 0.52 Ovr18GAOvary 14 1.07 Ovr20GA Ovary 15 1.88 Ovr25GA Ovary 16 2.52 Ovr206I Ovary17 2.51 Ovr32RA Ovary 18 3.01 Ovr35GA Ovary 19 5.17 Ovr40G Ovary 20 0.45Ovr50GB Ovary 21 2.69 OvrC087 Ovary 22 0.47 OvrC179 Ovary 23 1.46OvrC004 Ovary 24 4.99 OvrC007 Ovary 25 13.36 OvrC109 Ovary 26 6.61MamS516 Mammary 16.39 13.74 Gland 1 MamS621 Mammary 826.70 4.60 Gland 2MamS854 Mammary 34.60 18.30 Gland 3 Mam59X Mammary 721.57 27.00 Gland 4MamS079 Mammary 80.73 5.10 Gland 5 MamS967 Mammary 6746.90 72.80 Gland 6MamS127 Mammary 7.00 20.00 Gland 7 MamB011X Mammary 1042.00 29.00 Gland8 Mam12B Mammary 1342.00 Gland 9 Mam82XI Mammary 507.00 Gland 10 MamS123Mammary 24.85 4.24 Gland 11 MamS699 Mammary 84.74 5.54 Gland 12 MamS997Mammary 482.71 11.84 Gland 13 Mam162X Mammary 15.73 10.59 Gland 14MamA06X Mammary 1418.35 8.20 Gland 15 Mam603X Mammary 294.00 Gland 16Mam699F Mammary 567.40 86.60 Gland 17 Mam12X Mammary 425.00 31.00 Gland18 MamA04 Mammary 2.00 Gland 19 Mam42DN Mammary 46.05 31.02 Gland 20Utr23XU Uterus 1 600.49 27.95 Utr85XU Uterus 2 73.52 18.83 Utr135XOUterus 3 178.00 274.00 Utr141XO Uterus 4 289.00 26.00 CvxNKS54 Cervix 12.47 0.61 CvxKS83 Cervix 2 1.00 2.00 CvxNKS18 Cervix 3 1.00 0.00 CvxNK23Cervix 4 5.84 14.47 CvxNK24 Cervix 5 20.32 33.13 End68X Endometrium167.73 544.96 1 End8963 Endometrium 340.14 20.89 2 End8XA Endometrium1.68 224.41 3 End65RA Endometrium 303.00 5.00 4 End8911 Endometrium1038.00 74.00 5 End3AX Endometrium 6.59 1.69 6 End4XA Endometrium 0.4315.45 7 End5XA Endometriuxn 17.81 388.02 8 End10479 Endometriuxn 1251.6031.10 9 End12XA Endometrium 312.80 33.80 10 Kid107XD Kidney 1 2.68 29.65Kid109XD Kidney 2 81.01 228.33 Kid10XD Kidney 3 0.00 15.30 Kid6XD Kidney4 18.32 9.06 Kid11XD Kidney 5 1.38 20.75 Kid5XD Kidney 6 30.27 0.19Liv15XA Liver 1 0.00 0.45 Liv42X Liver 2 0.81 0.40 Liv94XA Liver 3 12.002.16 Lng LC71 Lung 1 5.45 3.31 LngAC39 Lung 2 1.11 0.00 LngBR94 Lung 34.50 0.00 LngSQ45 Lung 4 15.03 0.76 LngC20X Lung 5 0.00 1.65 LngSQ56Lung 6 91.77 8.03 ClnAS89 Colon 1 0.79 7.65 ClnC9XR Colon 2 0.03 0.00ClnRC67 Colon 3 0.00 0.00 ClnSG36 Colon 4 0.81 0.35 ClnTX89 Colon 5 0.000.00 ClnSG45 Colon 6 0.00 0.06 ClnTX01 Colon 7 0.00 0.00 Pan77X Pancreas1 0.89 2.62 Pan71XL Pancreas 2 3.99 0.12 Pan82XP Pancreas 3 59.92 28.44Pan92X Pancreas 4 17.21 0.00 StoAC93 Stomach 1 7.54 6.43 StoAC99 Stomach2 19.49 3.19 StoAC44 Stomach 3 3.62 0.37 SmI21XA Small 0.00 0.00Intestine 1 SmIH89 Small 0.00 0.00 Intestine 2 Bld32XK Bladder 1 0.000.21 Bld46XK Bladder 2 0.36 0.32 BldTR17 Bladder 3 0.28 0.00 Tst39XTestis 11.24 2.24 Pro84XB Prostate 1 2.60 24.30 Pro90XB Prostate 2 1.402.000.00=Negative

Table 2 and Table 3 represent a combined total of 187 samples in 16different tissue types. In the analysis of matching samples, the higherlevels of expression were in mammary gland, uterus, endometrium andovary, showing a high degree of tissue specificity for the gynecologictissues. Of all the samples different than those mentioned beforeanalyzed, only a few samples (Kid109XD, LngSQ56, and Pan82XP) showedhigh levels of expression of Ovr110.

Furthermore, the level of mRNA expression was compared in cancer samplesand the isogenic normal adjacent tissue from the same individual. Thiscomparison provides an indication of specificity for the cancer stage(e.g. higher levels of mRNA expression in the cancer sample compared tothe normal adjacent). Table 3 shows overexpression of Ovr110 in 15 of 16mammary gland cancer tissues compared with their respective normaladjacent (mammary gland samples MamS516, MamS621, MamS854, Mam59X,MamS079, MamS967, MamB011X, MamS123, MamS699, MamS997, Mam162X, MamA06X,Mam699F, Mam12X, and Mam42DN). There was overexpression in the cancertissue for 94% of the mammary gland matching samples tested.

For uterus, Ovr110 is overexpressed in 3 of 4 matching samples (uterussamples Utr23XU, Utr85XU, and Utr141XO). There was overexpression in thecancer tissue for 75% of the uterus matching samples analyzed.

For endometrium, Ovr110 is overexpressed in 6 of 10 matching samples(endometrium samples End8963, End65RA, End8911, End3AX, End10479, andEnd12XA). There was overexpression in the cancer tissue for 60% of theendometrium matching samples.

For ovary, Ovr110 shows overexpression in 1 of 1 matching sample. Forthe unmatched ovarian samples, 8 of 12 cancer samples show expressionvalues of Ovr110 higher than the median (2.52) for the normal unmatchedovarian samples. There was overexpression in the cancer tissue for 67%of the unmatched ovarian samples.

Altogether, the level of tissue specificity, plus the mRNAoverexpression in most of the matching samples tested are indicative ofOvr110 (including SEQ ID NO:1, 10, 11, 12 or 13) being a diagnosticmarker for gynecologic cancers, specifically, mammary gland or breast,uterine, ovarian and endometrial cancer.

Measurement of Ovr114; Clone ID1649377; Gene ID 481154 (SEQ ID NO:3)

The numbers depicted in Table 4 are relative levels of expression in 12normal tissues of Ovr114 compared to pancreas (calibrator). These RNAsamples were obtained commercially and were generated by pooling samplesfrom a particular tissue from different individuals. TABLE 4 RelativeLevels of Ovr114 Expression in Pooled Samples Tissue Normal Colon 2.3Endometrium 7.6 Kidney 0.5 Liver 0.6 Ovary 5.2 Pancreas 1.0 Prostate 2.1Small Intestine 1.3 Spleen 2.4 Stomach 1.5 Testis 15.8 Uterus 8.8

The relative levels of expression in Table 4 show that Ovr114 mRNAexpression is detected in all the pools of normal tissues analyzed.

The tissues shown in Table 4 are pooled samples from differentindividuals. The tissues shown in Table 5 were obtained from individualsand are not pooled. Hence the values for mRNA expression levels shown inTable 4 cannot be directly compared to the values shown in Table 5.

The numbers depicted in Table 5 are relative levels of expression ofOvr114 compared to pancreas (calibrator), in 46 pairs of matchingsamples and 27 unmatched tissue samples. Each matching pair contains thecancer sample for a particular tissue and the normal adjacent tissuesample for that same tissue from the same individual. In cancers (forexample, ovary) where it was not possible to obtain normal adjacentsamples from the same individual, samples from a different normalindividual were analyzed. TABLE 5 Relative Levels of Ovr114 Expressionin Individual Samples Normal & Borderline Matching Normal Tissue SampleID Cancer Type Cancer Malignant Adjacent Ovary 1 Ovr1037O/1038OPapillary serous 17.04 3.93 adenocarcinoma, G3 Ovary 2 OvrG021SPI/SN2Papillary serous 1.62 4.34 adenocarcinoma Ovary 3 OvrG010SP/SN Papillaryserous 0.50 1.12 adenocarcinoma Ovary 4 OvrA081F/A082D Mucinous tumor,low 0.84 0.96 malignant potential Ovary 5 OvrA084/A086 Mucinous tumor,grade G-B, 5.24 6.00 borderline Ovary 6 Ovr14604A1C Serouscystadenofibroma, 5.33 low malignancy Ovary 7 Ovr14638A1C Follicularcysts, low 8.11 malignant potential Ovary 8 Ovr1040O Papillary serous13.27 adenocarcinoma, G2 Ovary 9 Ovr1157O Papillary serous 106.08adenocarcinoma Ovary 10 Ovr1005O Papillary serous 77.04endometricarcinoma Ovary 11 Ovr1028O Ovarian carcinoma 14.78 Ovary 12Ovr14603A1D Adenocarcinoma 22.23 Ovary 13 Ovr9410C360 Endometrioid 4.74adenocarcinoma Ovary 14 Ovr1305X Papillary serous 96.49 adenocarcinomaOvary 15 Ovr773O Papillary serous 8.40 adenocarcinoma Ovary 16 Ovr988ZPapillary serous 6.40 adenocarcinoma Ovary 17 Ovr9702C018GA NormalCystic 12.06 Ovary 18 Ovr2061 Normal left atrophic, 10.11 small cysticOvary 19 Ovr9702C020GA Normal-multiple ovarian 12.70 cysts Ovary 20Ovr9702C025GA Normal-hemorrhage CL cysts 22.09 Ovary 21 Ovr9701C050GBNormal-multiple ovarian 9.01 cysts Ovary 22 Ovr9701C087RA Normal-smallfollicle 1.86 cysts Ovary 23 Ovr9702C032RA 7.81 Ovary 24 Ovr9701C109RANormal 1.50 Ovary 25 Ovr9411C057R Benign large endometriotic 5.22 cystOvary 26 Ovr9701C179a Normal 3.09 Ovary 27 Ovr1461O Serouscystadenofibroma, 3.53 no malignancy Ovary 28 Ovr9701C035GA Normal 6.32Ovary 29 Ovr9702C007RA Normal 0 Ovary 30 Ovr9701C087RA Normal-smallfollicle 1.97 cysts Ovary 31 Ovr9411C109 Normal 9.49 Ovary 32Ovr9701C177a Normal-cystic follicles 3.85 Endometrium 1 End14863A1A/A2AModerately differ. Endome. 1.30 0.70 carcinoma/NAT Endometrium 2End9709C056A/55A Endometrial 1.83 11.90 adenocarcinoma/NAT Endometrium 3End9704C281A/2A Endometrial 13.32 7.76 adenocarcinoma/NAT Endometrium 4End9705A125A/6A Endometrial 3.62 3.34 adenocarcinoma/NAT Mammary Gland 1Mam00042D01/N01 3.13 0.76 Mammary Gland 2 MamS99-522A/B 4.45 0.45Mammary Gland 3 Mam1620F/1621F 0.74 1.91 Mammary Gland 4 Mam4003259a/g3.48 2.00 Uterus 1 Utr850U/851U Stage 1 endometrial 46.96 11.96cancer/NAT Uterus 2 Utr233U96/234U96 Adenocarcinoma/NAT 20.02 5.90Uterus 3 Utr1359O/1358O Tumor/NAT 10.23 7.74 Uterus 4 Utr1417O/1418OMalignant tumor/NAT 7.52 4.92 Cervix 1 CvxVNM00083/83 Keratinizingsquamous cell 5.47 14.31 carcinoma Cervix 2 CvxIND00023D/N Large cellnonkeratinizing 4.99 3.99 carcinoma Cervix 3 CvxIND00024D/N Large cellnonkeratinizing 10.14 14.22 carcinoma Bladder 1 Bld665T/664T 1.43 4.03Bladder 2 Bld327K/328K Papillary transitional 1.15 0.99 cellcarcinoma/NAT Kidney 1 Kid4003710C/F 0.03 0.35 Kidney 2 Kid1242D/1243D1.61 0.14 Lung 1 Lng750C/751C Metastatic osteogenic 2.44 5.73sarcoma/NAT Lung 2 Lng8890A/8890B Cancer/NAT 1.11 5.19 Lung 3Lng9502C109R/10R 1.99 0.80 Liver 1 Liv1747/1743 Hepatocellular 0.67 1.07carcinoma/NAT Liver 2 LivVNM00175/175 Cancer/NAT 15.46 2.85 Skin 1Skn2S9821248A/B Secondary malignant 2.83 0.70 melanoma Skin 2Skn4005287A1/B2 0.91 4.02 Small Int. 1 SmI9802H008/009 0.87 0.82 Stomach1 Sto4004864A4/B4 Adenocarcinoma/NAT 0.81 1.22 Stomach 2 StoS9822539A/BAdenocarcinoma/NAT 1.22 1.39 Stomach 3 StoS99728A/C Malignantgastrointestinal 0.47 0.35 stromal tumor Prostate 1 Pro1012B/1013BAdenocarcinoma/NAT 2.39 2.61 Prostate 2 Pro1094B/1095B 0.10 0.38Pancreas 1 Pan776p/777p Tumor/NAT 2.39 0.52 Pancreas 2 Pan824p/825pCystic adenoma 1.66 1.22 Testis 1 Tst239X/240X Tumor/NAT 1.24 1.72 Colon1 Cln9706c068ra/69ra Adenocarcinoma/NAT 0.38 0.65 Colon 2Cln4004732A7/B6 Adenocarcinoma/NAT 0.44 1.26 Colon 3 Cln4004695A9/B81.94 1.53 Colon 4 Cln9612B006/005 Asc. Colon, Cecum, 3.38 1.10adenocarcinoma Colon 5 Cln9704C024R/25R Adenocarcinoma/NAT 1.66 2.77Table 4 and Table 5 represent a combined total of 129 samples in 17human tissue types. Among 117 samples in Table 5 representing 16different tissues high levels of expression are seen only in ovariancancer samples. The median expression of Ovr114 is 14.03 (range:0.5-106.08) in ovarian cancer and 4.34 (range: 0-22.09) in normalovaries. In other words, the median expression levels of Ovr114 incancer samples is increased 3.5 fold as compared with that of the normalovarian samples. Five of 12 ovarian cancers (42%) showed increasedexpression relative to normal ovary (with 95% specificity). The medianexpression of Ovr114 in other gynecologic cancers is 4.99, and 2 out of15 samples showed expression levels comparable with that in ovariancancer. The median of the expression levels of Ovr114 in the rest of thecancer samples is 1.24, which is more than 11 fold less than thatdetected in ovarian cancer samples. No individual showed an expressionlevel comparable to that of ovarian cancer samples (except Liver 2;LivVNM00175/175).

The 3.5 fold increase in expression in 42% of the individual ovariancancer samples and no compatible expression in other non-gynecologiccancers is indicative of Ovr114 being a diagnostic marker for detectionof ovarian cancer cells. It is believed that the Ovr114 marker may alsobe useful in detection of additional gynecologic cancers.

Measurement of Ovr115; Clone ID1283171; Gene ID 332459 (SEQ ID NO:2 or14)

The numbers depicted in Table 6 are relative levels of expression Ovr115compared to their respective calibrators. The numbers are relativelevels of expression in 12 normal tissues of ovaries compared to Testis(calibrator). These RNA samples were obtained commercially and weregenerated by pooling samples from a particular tissue from differentindividuals. TABLE 6 Relative Levels of Ovr115 Expression in PooledSamples Tissue Normal Colon 858.10 Endometrium 12.34 Kidney 3.76 Liver0.00 Ovary 0.43 Pancreas 0.00 Prostate 8.91 Small Intestine 62.25 Spleen0.00 Stomach 37.53 Testis 1.00 Uterus 47.67

The relative levels of expression in Table 6 show that Ovr115 mRNAexpression is detected in all the 12 normal tissue pools analyzed.

The tissues shown in Table 6 are pooled samples from differentindividuals. The tissues shown in Table 7 were obtained from individualsand are not pooled. Hence the values for mRNA expression levels shown inTable 6 cannot be directly compared to the values shown in Table 7.

The numbers depicted in Table 7 are relative levels of expression ofOvr115 compared to testis (calibrator), in 46 pairs of matching samplesand 27 unmatched tissue samples. Each matching pair contains the cancersample for a particular tissue and the normal adjacent tissue sample forthat same tissue from the same individual. In cancers (for example,ovary) where it was not possible to obtain normal adjacent samples fromthe same individual, samples from a different normal individual wereanalyzed. TABLE 7 Relative Levels of Ovr115 Expression in IndividualSamples Normal & Borderline Matching Normal Tissue Sample ID Cancer TypeCancer Malignant Adjacent Ovary 1 Ovr1037O/1038O Papillary serous 193.340.24 adenocarcinoma, G3 Ovary 3 OvrG021SPI/SN2 Papillary serous 0.380.31 adenocarcinoma Ovary 4 OvrG010SP/SN Papillary serous 231.25 0.45adenocarcinoma Ovary 2 OvrA084/A086 Mucinous tumor, grade G- 143.3416.65 B, borderline Ovary 5 OvrA081F/A082D Mucinous tumor, low 314.13 0malignant potential Ovary 19 Ovr14604A1C Serous cystadenofibroma, 299.87low malignancy Ovary 26 Ovr14638A1C Follicular cysts, low 1278.32malignant potential Ovary 6 Ovr1040O Papillary serous 144.25adenocarcinoma, G2 Ovary 22 Ovr9410C360 Endometrioid 0.29 adenocarcinomaOvary 23 Ovr1305X Papillary serous 157.41 adenocarcinoma Ovary 27Ovr773O Papillary serous 340.04 adenocarcinoma Ovary 28 Ovr988ZPapillary serous 464.75 adenocarcinoma Ovary 7 Ovr1157O Papillary serous432.07 adenocarcinoma Ovary 8 Ovr1005O Papillary serous 74.23endometricarcinoma Ovary 9 Ovr1028O Ovarian carcinoma 1408.79 Ovary 10Ovr14603A1D Adenocarcinoma 0.00 Ovary 11 Ovr9702C018GA Normal Cystic0.16 Ovary 12 Ovr2061 Normal left atrophic, 0.00 small cystic Ovary 13Ovr9702C020GA Normal-multiple ovarian 0.00 cysts Ovary 14 Ovr9702C025GANormal-hemorrhage CL 0.00 cysts Ovary 15 Ovr9701C050GB Normal-multipleovarian 0.91 cysts Ovary 16 Ovr9701C087RA Normal-small follicle 0.00cysts Ovary 17 Ovr9702C032RA 0.28 Ovary 18 Ovr9701C109RA Normal 0.00Ovary 20 Ovr9411C057R Benign large 38.87 endometriotic cyst Ovary 21Ovr9701C179a Normal 0.08 Ovary 24 Ovr1461O Serous cystadenofibroma, 0.00no malignancy Ovary 25 Ovr9701C035GA Normal 0.00 Ovary 29 Ovr9702C007RANormal 0.00 Ovary 30 Ovr9701C087RA Normal-small follicle 0.00 cystsOvary 31 Ovr9411C109 Normal 0.00 Ovary 32 Ovr9701C177a Normal-cysticfollicles 0.00 Uterus 1 Utr850U/851U Stage 1 endometrial 39.95 13.60cancer/NAT Uterus 2 Utr233U96/234U96 Adenocarcinoma/NAT 140.37 22.67Uterus 3 Utr1359O/1358) Tumor/NAT 16.45 32.50 Uterus 4 Utr1417O/1418OMalignant tumor/NAT 288.52 5.29 Endometrium 1 End14863A1A/A2A Moderatelydiffer. 2.61 6.24 Endome. carcinoma/NAT Endometrium 2 End9709C056A/55AEndometrial 2.10 49.40 adenocarcinoma/NAT Endometrium 3 End9704C281A/2AEndometrial 480.77 19.22 adenocarcinoma/NAT Endometrium 4End9705A125A/6A Endometrial 322.07 31.08 adenocarcinoma/NAT Lung 1Lng750C/751C Metastatic osteogenic 38.81 7.36 sarcoma/NAT Lung 2Lng8890A/8890B Cancer/NAT 690.12 14.71 Lung 3 Lng9502C109R/10R 1756.902.86 Skin 1 Skn2S9821248A/B Secondary malignant 10.56 0.00 melanoma Skin2 Skn4005287A1/B2 331.30 47.23 Prostate 1 Pro1012B/1013BAdenocarcinoma/NAT 14.64 4.39 Prostate 2 Pro1094B/1095B 0.09 2.54Bladder 1 Bld665T/664T 404.56 90.20 Bladder 2 Bld327K/328K Papillarytransitional 77.35 177.37 cell carcinoma/NAT Kidney 1 Kid4003710C/F 0.1712.72 Kidney 2 Kid1242D/1243D 0.00 13.74 Mammary Gland 1 Mam1620F/1621F0.27 0.12 Mammary Gland 2 Mam4003259a/g 5.71 0.00 Liver 1 Liv1747/1743Hepatocellular 0.14 0.69 carcinoma/NAT Liver 2 LivVNM00175/175Cancer/NAT 0.00 0.00 Small Int. 1 SmI9802H008/009 128.44 151.38 Stomach1 Sto4004864A4/B4 Adenocarcinoma/NAT 303.01 116.72 Stomach 2StoS9822539A/B Adenocarcinoma/NAT 24.12 17.76 Stomach 3 StoS99728A/CMalignant 0.00 9.10 gastrointestinal stromal tumor Pancreas 1Pan776p/777p Tumor/NAT 0.00 0.43 Pancreas 2 Pan824p/825p Cystic adenoma0.00 3.17 Testis 1 Tst239X/240X Tumor/NAT 24.05 1.37 Colon 1Cln9706c068ra/69ra Adenocarcinoma/NAT 605.60 169.77 Colon 2Cln4004732A7/B6 Adenocarcinoma/NAT 367.20 281.32 Colon 3 Cln4004695A9/B8316.15 295.77 Colon 4 Cln9612B006/005 Asc. Colon. Cecum, 820.89 543.52adenocarcinoma Colon 5 Cln9704C024R/25R Adenocarcinoma/NAT 161.18 150.07Cervix 1 CvxVNM00083/83 Keratinizing squamous 738.17 1195.88 cellcarcinoma Cervix 2 CvxIND00023D/N Large cell 1473.04 1229.80nonkeratinizing carcinoma Cervix 3 CvxIND00024D/N Large cell 2877.481275.02 nonkeratinizing carcinomaTable 6 and Table 7 represent a combined total of 129 samples in 17human tissue types. Comparisons of the level of mRNA expression inovarian cancer samples and the normal adjacent tissue from the sameindividuals or normal tissues from other individuals are shown in Table7. Ovr115 was expressed at higher levels in 9 of 12 cancer tissues(75%), relative to the maximum level detected in all 21 normal or normaladjacent ovarian samples. All 4 of 4 (100%) ovarian tumors withborderline malignancy had elevated Ovr115 expression. The medianexpression in ovarian cancers (including the ones with borderlinemalignancy) was 212.30 while the median expression in normal ovaries was0. When compared with their own normal adjacent tissue samples,expression levels of Ovr115 were also elevated in 3 of 3 (100%) lungcancers, 3 of 4 (75%) uterus cancers and 2 of 4 (50%) endometrialcancers.

The relatively high expression levels of Ovr115 in ovarian and otherselected cancer samples is indicative of Ovr115 being a diagnosticmarker for detection of ovarian, lung, uterine and endometrial cancer.

A homolog of Ovr115 has also been identified in public data base;g2597613 as gi|25076121gb|U75329.1|HSU75329 Human serine protease mRNA,complete CDS. This homolog is depicted herein as SEQ ID NO:9. It isbelieved that SEQ ID NO:9 or the protein encoded thereby (SEQ ID NO:15)may also be useful as a diagnostic marker for detection of ovarian,lung, uterine and endometrial cancer in human patients.

1. A method for detecting the presence of a selected cancer in a patientcomprising: (a) measuring levels of CSG in cells, tissues or bodilyfluids in a patient; and (b) comparing the measured levels of CSG withlevels of CSG in cells, tissues or bodily fluids from a normal humancontrol, wherein a change in measured levels of CSG in said patientversus normal human control is associated with the presence of aselected cancer. 2-5. (canceled)
 6. The method of claim 1 wherein theCSG comprises SEQ ID NO:1, 10, 11, 12, 13 or 16 and the selected canceris a gynecologic cancer selected from the group consisting of breast,ovarian, endometrial and uterine cancer.
 7. The method of claim 1wherein the CSG comprises SEQ ID NO:2, 9 or 14 and the selected canceris lung cancer or a gynecologic cancer selected from the groupconsisting of ovarian, endometrial and uterine cancer.
 8. The method ofclaim 1, wherein the CSG comprises SEQ ID NO:1, 2, 3, 9, 10, 11, 12, 13,14 or 16 and the selected cancer is ovarian cancer.
 9. An antibodyagainst a CSG wherein said CSG comprises SEQ ID NO:1, 2, 3, 9, 10, 11,12, 13, 14 or
 16. 10. A method of imaging or treating a selected cancerin a patient comprising administering to the patient an antibody ofclaim
 9. 11. The method of claim 10 wherein said antibody is labeledwith paramagnetic ions or a radioisotope.
 12. (canceled)
 13. The methodof claim 10 wherein the antibody is conjugated to a cytotoxic agent.